Lower alkoxymethyl esters of 2,4,6-triiodobenzoic acid derivatives

ABSTRACT

Esters of certain 2,4,6-triiodobenzoic acid derivatives are useful as X-Ray contrast media. Representative compounds are the ethoxymethyl esters of acetrizoic, iothalamic and iodobenzamic acids.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the field of organic chemistry and moreparticularly to novel esters useful as nonionic X-Ray contrast media.

2. Description of the Prior Art

Various derivatives of 2,4,6-triiodobenzoic acid are known to be usefulas X-Ray contrast media, for example, those esters described in U.S.Pat. No. 3,795,698.

One of the disadvantages asociated with certain known contrast media isthat after they are administered they are immediately absorbed by thebody with a corresponding decrease in time available for radiography.Others are too hydrolytically stable and will remain in the body forextended periods of time although there is sufficient time forradiography.

Accordingly, nonionic X-Ray contrast media that remain in the body onlyfor a sufficient time for adequate radiography would be an advancementin the art.

BRIEF DESCRIPTION OF THE INVENTION

Accordingly, the present invention is directed to compounds representedby the following formula which are useful as nonionic X-ray contrastmedia. ##STR1## wherein, a is an integer from 1 to 3, b is 0 or 1, R isan aryl or substituted aryl, R₁ is

(1) ##STR2## wherein R₂ is hydrogen or an alkyl, R₃ is alkyl orsubstituted alkyl; or

(2) a cyclic glycosyl represented by the following formula; ##STR3##wherein R₄ is hydrogen or an acyl group and m is 2 or 3, X and Y areindividually nonionizing functions compatible with low toxicity and/orwater solubility in the 2,4,6-triiodophenyl configuration.

The novel compounds of this invention after administration to an animalor human hydrolyze at appropriate rates and are not immediatelyabsorbed. Therefore, they remain in position in the body cavity for asufficient time for adequate radiography. Thereafter, they hydrolyze towater-soluble nontoxic products which are excreted via usual bodymechanisms. Additionally the degree of hydrolytic stablity needed can bevaried depending upon the radiographic technique to be employed, e.g.,lymphangiography 1 to 2 hours, bronchiography 1/2 to 1 hour. Lastly, thecompounds of this invention are adequately stable to basic media. Inother words, these compounds provide greater flexibility in terms of (a)selective biodegradation and (b) formulations.

DETAILED DESCRIPTION OF THE INVENTION

As mentioned R is an aryl or substituted aryl. Examples include phenyland phenyl substituted with a lower alkyl radical or with an alkoxyradical containing 1 to 6 carbon atoms. Specific examples include benyl,methyl phenyl and ethyl phenyl.

R₂ and R₃ may be alkyl or substituted groups. Illustrative alkyl groupsinclude linear or branched alkyl groups containing 1 to 10 carbon atoms.Lower alkyl groups are preferred--that is those containing 1 to 6 carbonatoms. Illustrative alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, amyl, isoamyl, hexyl, heptyl, nonyl or decyl.

Illustrative substituted alkyl groups include aralkyl such asphenylalkyl containing 1 to 6 carbon atoms in the alkyl group. Specificexamples include phenylmethyl and phenylethyl.

R₄ may be an acyl radical containing 2 to 10 carbon atoms, preferably 2to 5 carbon atoms. Representative acyl groups include acetyl, butanoyl,pentanoyl, heptanoyl and decanoyl.

Representative cyclic glycosyl radicals includeper-O-acyl-aldopentopyronasyl, and per-O-acylaldohexofuranosyl, such as,

2,3,4-tri-O-acetyl-β-D-arabinopyranosyl;

2,3,4-tri-O-acetyl-β-D-xylopyranosyl;

3,4,6-tri-O-acetyl-β-D-glucopyranosyl;

2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl,

and others described on pages 214-215 of J. Stanck, et al., TheMonosaccharides, Academic Press, New York, N.Y. 1963.

As mentioned, the substituent in the 3 and 5 positions of the ring,namely X and Y are nonionizing functions compatible with low toxicityand/or water-solubility in the 2,4,6-triiodophenyl configuration. As isknown by those skilled in the art, the term "detoxifying and/orsolubilizing groups" has been used as a generic designation for asubstantial number of functional groups whose occurrence in themeta-position in a 2,4,6-triiodinated moiety has come to be associatedwith compounds which exhibit a relatively low toxicity and/or arelatively high water solubility (cf. G. B. Hoey, P. E. Wiegert and R.D. Rands, Jr., "Organic Iodine Compounds as X-Ray contrast media:, inInternational Encyclopedia of Pharmacology and Therapeutics, Section 76,"Radio-contrast Agents", P. K. Knoefel, Section Editor, Pergamon Press;Vol. 1, pp, 23-40, 54-73 (1971). While the use of such terminologyoriginated in connection with 2,4,6-triiodobenzoic acid derivativespossessing relatively low toxicity and/or relatively high watersolubility, the results set forth herein are consistent with the viewthat substantially the same nonionizing functions are also compatiblewith low toxicity and/or water solubility in the tiiodinated moiety ofthe nonionic compounds of the present invention. Furthermore thecompounds of this invention do undergo hydrolysis to non-toxic,water-soluble X-ray contrast media.

Among the nonionizing functions which may constitute X and Y may bementioned the following: lower alkoxy, e.g., methoxy and ethoxy;hydroxy-(lower alkoxy), e.g., 2-hydroxy-ethoxy; lower alkoxy-(loweralkoxy), e.g., methoxy-ethoxy and ethoxy-propoxy; lower acylamino, e.g.,acetamido and propionamido; lower acylamino-(lower alkyl), e.g.,acetamidomethyl and acetamidoethyl; lower acylamino-(lower acylamino),e.g., aceturamido; hydroxy-lower acylamino, e.g., hydroxyacetamido andhydroxy-propionamido; N-(lower alkyl)-lower acylamino, e.g.,N-methylacetamido and N-methyl-propionamido; lower alkylsulfonamido,e.g., methylsulfonamido and ethylsulfonamido; N-(lower alkyl)-loweralkylsulfonamido, e.g., N-methylethylsulfonamido andN-ethyl-methylsulfonamido; 3,3-bis(lower alkyl)-ureido, e.g.,3,3-dimethylureido and 3-methyl-3-ethylureido; lower perfluoroacylamino,e.g., perfluroacetamido and perfluoropropionamido; carbamyl; N-(loweralkyl) carbamyl, e.g., N-methylcarbamyl and N-ethylcarbamyl;N,N-di-(lower alkyl) carbamyl, e.g., N,N-dimethylcarbamyl andN,N-diethylcarbamyl; lower alkoxy-(lower acylamino), e.g.,methoxyacetamido and ethoxyacetamido; lower alkoxy-alkoxy-(loweracylamino), e.g., methoxy-ethoxy(acetamido); hydroxy and hydroxy-loweralkyl, e.g., hydroxy-methyl and hydroxyethyl. As used herein, the term"lower" (e.g., lower alkyl and lower alkoxy) means that the functioncontains between 1 and 6 carbon atoms. These skilled in the art willrecognize that functions of the above type other than those specificallyenumerated may also constitute X and Y.

Representative compounds of this invention include

Butoxymethyl 3-Acetamido-2,4,6-triiodobenzoate;

Heptoxymethyl 3-Acetamido-2,4,6-triiodobenzoate;

1-Ethoxyethyl 3-Acetamido-2,4,6-triiodobenzoate;

1-Hexoxypropyl 3-Acetamido-2,4,6-triiodobenzoate;

Propoxymethyl 3-Acetamido-2,4,6-triiodo-N-methylisophthalamate;

1-Pentoxyethyl 3-Acetamido-2,4,6-triiodo-N-methylisophthalamte;

Octaoxymethyl 3-Acetamido-2,4,6-triiodo-N-methylisophthalamate;

2,3,4,6-tetra-O-propanoyl-glucopyranosyl3-Acetamido-2,4,6-triiodo-N-methylisophthalamate;

2,3,5,6-tetra-O-acetyl galactafuranosyl3-Acetamido-2,4,6-triiodo-N-methyl isophthalamate;

2,3,5,6-tetra-O-acetyl arabinopyranosyl3-Acetamido-2,4,6-triiodo-N-methyl isophthalamate;

1-Ethoxyethyl 3-(3-Amino-2,4,6-triiodo-N-phenylbenzamido)propionate;

Butoxymethyl 3-(3-Amino-2,4,6-triiodo-N-phenylbenzamido)propionate;

1-Hexoxyethyl 3-(3-Amino-2,4,6-triiodo-N-phenylbenzamido)propionate.

The above mentioned novel compounds may be prepared by reacting anα-halo acylic or cyclic ether with the appropriate triiodobenzoic acidderivative. α-bromo or α-chloro ethers are preferred. Such a reaction isstraightforward as will be appreciated by those skilled in the art andneed not be described in more detail here.

The novel compounds of this invention may be used as X-ray contrastagents in various radiographic procedures including those involvingbronchiography, lymphography, gastrointestinal radiography, myelography,hepatography and urography. They are relatively water insoluble but canhydrolyze in vivo at various rates to provide non-toxic, water soluble,X-ray contrast media (as well as other products) which are safely andrapidly excreted by the normal mechanisms for such compounds, forexample, in bronchiography.

The following examples illustrate the invention.

EXAMPLE I Preparation of Ethoxymethyl 3-Acetamido-2,4,6-triiodobenzoate

A. Preparation of Chloromethyl Ethyl Ether ##EQU1## Essentially, theprocedure of J. Farren, H. Fife, F. Clark & C. Carlard, J. Am. Chem.Soc., 47, 242 (1925) was used.

Paraformaldehyde (1 lb., 15.08 gram-moles of CH₂ O) and 100% ethanol(696 g., 15.08 mole) were slurried in a 3-liter, three-necked flaskequipped with a stirrer, gas inlet tube, thermometer, condenser anddrying tube. The reaction was stirred and cooled in an ice bath andanhydrous hyrogen chloride (692 g.) was passed in until all theparaformaldehyde had dissolved. The layers were separated and theorganic layer was dried over CaCl₂ for 11/2 hours. The CaCl₂ wasfiltered and dry nitrogen was bubbled through for 11/2 hours to driveout excess HCl. The crude chloromethyl ether was distilled rapidlywithout fractionation and with dry nitrogen bubbling throughcontinuously. During the distillation, some paraformaldehyde collectedin the condenser. The fraction boiling at 79°-82° C. was redistilled inthe same manner. The material boiling at 82°-92° C. was fractionallydistilled through a 20-in. column packed with helices. Three fractionswere obtained:

I. BP 70°-81°; n_(D) ²⁶.2 1.4000,

II. BP 81°-82° ; n_(D) ²⁵.5 1.4007,

III. BP 82°-83°; n_(D) ²⁶ 1.4007, [Farren, Loc. cit., b.p. 81°-82°;Littershield, Ann., 330, 122(1904), b.p. 83°, n_(D) ²⁰ 1.4040; L. S.Summers, Chem. Revs., 55, 304 (1955), b.p. 84°, n_(D) ¹⁸ 1.4040].

Fractions II and III totaled 692.9 g. (yield 48.7%). The liquid wasstored over CaCO₃ to consume any HCl evolved and thus retarddecomposition.

B. Preparation of Ethoxymethyl 3-Acetamido-2,4,6-triiodobenzoate##STR4##

To a stirred slurry of sodium 3-acetamido-2,4,6-triiodobenzoate (14.5 g,0.025 mole) in dimethylformamide (150 ml) was added chloromethyl ethylether (2.56 g, 0.027 mole). A white solid (NaCl) precipitated promptly.The mixture was stirred overnight, filtered, and evaporated to neardryness under reduced pressure to yield 17.8 g. of residue. The residuewas dissolved in 200 ml. of chloroform, filtered and the filtrate wasextracted with 5% aqueous sodium bicarbonate, washed with water anddried over anhydrous sodium sulfate and evaporated under reducedpressure to dryness. The residue (10.5 g.) obtained was recrystallizedfrom carbon tetrachloride (200 ml.) and chloroform (enough to dissolvethe residue), to yield the product 5.05 g. (31.5%), m.p. 174°-177.7° C.The ir and and nmr spectra were in agreement with the structure asassigned.

Anal. Calcd. for C₁₂ H₁₂ I₃ NO₄ : C, 23.43; H, 1.97; I, 61,91; N, 2.28.

Found: C, 23.42; H, 1.91; I, 62.20; N, 2.26.

EXAMPLE II Preparation of Ethoxymethyl 3-Acetamido-N-methyl2,4,6-triiodoisophthalamate ##STR5##

Chloromethyl ethyl ether (102.6 g., 1.09 moles, 100 ml.) was added in 5minutes to a stirred solution of the sodium salt of iothalamic acid(635.9 g., 1 mole) in 6 l. of dimethylformamide. Some fumes were evolvedand there was an immediate precipitate. After stirring for about 1.5hours dimethylformamide was removed under reduced pressure. The residuewas dissolved in 6.5 l. of chloroform and 1.5 l. of dimethylformamideand was extracted twice with 4 l. of 5% aqueous sodium bicarbonate. Thechloroform layer was dried over sodium sulfate and magnesium sulfateovernight and the solvent was removed under reduced pressure. Yield was433.1 g. of nearly pure product.

The crude product was recrystallized from 250 ml. of dimethylformamideand 4600 ml. of carbon tetrachloride to yield 242 g. (36%) of product,decomposes 275°-280° C. Tlc showed a single spot with a trace ofiothalamic acid; ir and nmr spectra confirmed the structure.

Anal. Calcd. for C₁₄ H₁₅ N₂ I₃ O₅ : C, 25.01; H, 2.25; N, 4.17; I,56.66. Found: C, 25.17; H, 2.35; N, 4.25; I, 56.35.

EXAMPLE III Preparation of EthoxymethylN-(3-Amino-2,4,6-triiodobenzoyl)-N-phenyl-3-aminopropionate ##STR6##

Sodium ethoxide was prepared from 1.74 g. (0.0756 g-atom) of sodium in2B ethanol (250 ml.). Iobenzamic acid (50 g., 0.0756 mole) and 250 ml.of 2B ethanol were added. After the iobenzamic acid dissolved, thesolution was evaporated to dryness under reduced pressure. An orangecolor developed during heating. The residue was dissolved in 500 ml. ofdimethylformamide and some of the dimethylformamide (75 ml.) wasevaporated (vacuum pump) to entrain any residual ethanol. The solutionwas cooled to 1.5° C. and chloromethyl ether (0.076 g., 7.2 ml.) wasadded in one portion. The temperature rose to 4.5° C., the red-browncolor changed to a rose color and a precipitate formed (the precipitatelater redissolved). The thin-layer (benzene-MEK-methanol, 60:25:10)chromatogram of this reaction product versus iobenzamic acid showed anew spot with a slightly greater R_(f) than iobenzamic acid. Someunreacted iobenzamic acid was present. Dimethylformamide was evaporated(vacuum pump), the residue was dissolved in chloroform (100 ml.), andextracted with 300 ml. of 5% sodium bicarbonate. Dimethylformamide (200ml.) was added and the extraction was repeated. Tlc confirmed the nearlycomplete removal of iobenzamic acid. All solvents were evaporated(vacuum pump). The residue (45 g.) was extracted with 700 ml. of ether.A brown insoluble residue was rejected. Petroleum ether was added toether solution until it was turbid.

After overnight stirring, a first crop of 26.00 g. (48%), m.p. 125°-127°C., was collected. A thin-layer of this material in two systems(benzene, methyl ethylketone, acetic acid (60:25:10); chloroformisopropanol, ammonium hydroxide (60:30:10) indicated it was free ofunreacted iobenzamic acid. The product was recrystallized fromtetrahydrofuran-pet ether to yield 19.1 g., m.p. 129°-132.5° C. The nmrand ir confirmed the structure.

Anal. Calcd. for C₁₉ H₁₉ I₃ N₂ O₄ : C, 31.69; H, 2.66; I, 52.87; N,3.82.

Found: C, 31.77; H, 2.71; I, 53.21; N, 3.79

EXAMPLE IV Preparation of 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl3-Acetamido-2,4,6-triiodo-N-methylisophthalamate ##STR7##

Sodium iothalamate (41.3 g., 0.065 mole) was dissolved in 400 ml. ofdimethylformamide. Tetraacetylglucosyl bromide (26.7 g., 0.067 mole) wasadded in one portion. There was no temperature rise. The course of thereaction was followed by thin-layer chromatography (system-benzenemethylethyl ketone-acetic acid 60:25:10). Aliquots were taken from thedimethylformamide reaction mixture, diluted with tetrahydrofuran andspotted versus a zero time sample of sodium iothalamate. After one hourstirring at room temperature, a single large spot with an R_(f) greaterthan Na iothalamate appeared (TLC system, 60 parts benzene--25 partsmethyl ethyl ketone--10 parts acetic acid). The thin-layer chromatogramdid not change after stirring overnight at room temperature or 11/2hours at 80° C. The dimethylformamide was evaporated (vacuum pump)leaving a glassy, foam-like residue. The residue was dissolved in 150ml. of dimethylformamide and 375 ml. of chloroform and extracted with360 ml. of 5% aqueous bicarbonate. The organic layer was separatedimmediately, dried with sodium sulfate overnight, and concentrated underreduced pressure leaving a residue of 48.8 g. Thin-layer chromatographyof this showed only a trace of iothalamic acid left (TLC system,benzene-methyl ethyl ketone-acetic acid, 60:25:10). The residue wascrystallized from 100 ml. of chloroform and 300 ml. of carbontetrachloride to yield a 1st crop of 20.5 g. and 2nd crop of 12.2 g.(TLC using the same system as above was identical with the 1st crop).Both crops were combined (30.6 g.) and recrystallized from 100 ml. ofTHF and 250 ml. of ether, yield 17.4 g., m.p. 171°-178° C. (dec). The irand nmr were in accord with the proposed structure.

Anals. Calcd. for C₂₅ H₂₇ I₃ N₂ O₁₃ : C, 31.80; H, 2.88; I, 40.32; H,2.96. Found: C, 32.03; H, 3.02; I, 39.38; N, 2.73.

EXAMPLE V

In order to study the hydrolytic stability of Example I, a 1 gram samplewas rolled with 75 ml. of phosphate buffer solution (pH 7.4) and glassbeads (to increase the surface area) for 16.5 hours. The pH fell to3.49. This demonstrated the aqueous instability of the ethoxymethylester linkage at physiological pH. A 1 gram sample of Example II wastreated in the same manner. After 16.5 hours of rolling in pH 7.4phosphate buffer, the pH had fallen to 2.56. The sample of Example IIhad virtually all dissolved, indicating complete hydrolysis.

EXAMPLE VI

1/2 gram of each of Example II, Example III and Example IV were rolled24 hours in 40 ml of pH 7.46 phosphate buffer solution with glass beads.The results are tabulated below. The slurries were examined bythin-layer chromatography (System chloroform-isopropyl alcohol-ammoniumhydroxide, 60:30:10).

                  TABLE I                                                         ______________________________________                                                Initial After                                                         Compound                                                                              pH      24 hrs. Appearance                                                                              TLC of Slurry                               ______________________________________                                        Example 7.40    7.48    Milky slurry                                                                            No decomposition                            III                                                                           Example 7.42    7.38    Milky slurry                                                                            Trace of                                    IV                                iothalamic acid                             Example 7.2     3.72    Dissolved All iothalamic                              II                                acid                                        ______________________________________                                    

EXAMPLE VII

A metabolism study was run on Examples II, III, and IV byintraperitoneally injecting 5-6.5 ml. of the Examples into rats.Radiographically, contrasts disappeared in 10 days for Example II, 35days and 15 days for Example IV.

EXAMPLE VIII

The LD₅₀ for Examples I-IV was determined by intraperitoneally injectingthe example compounds into mice. For Example I it was 3119 mg/kg andsmall amounts of the compound were found in the abdominal cavity atnecropsy. For Example II, it was 16,000 mg/kg±977 and traces of thecompound were found in the peritoneally cavity at necropsy. For ExampleIII and IV they were greater than 10,000 mg/kg.

EXAMPLE IX

An excretion study was determined for Examples I and II by injectingcompunds of Examples I and II (equivalent to 500 mg/kg of I₂)intraperitoneally into 3 small rats. For Example I, 71.27% of the iodineinjected was recovered over a 96 hour period in urine, feces and theperitoneally washings obtained at necropsy. Most excretion occurred in48 hours. At necropsy some adhesions of the intestines and and someliver damage was evident. For Example II, 73.6% was recovered over a 96hour period with most of the excretion occurring in 48 hours. Atnecropsy some adhesions of the intestines and some liver damage wasevident.

EXAMPLE X

A lymphogram of a dog was made after injecting two milliliters ofExample I subcutaneously and 9.6 milliliters intraperitoneally. Poor tomoderate visualization resulted. Another lymphogram of a dog was madeafter injecting 2.5 grams intralymphatically. Six x-rays were taken. Nocontrast medium passed at the first (popliteal) node in 24 hours atwhich time the dog was sacrificed.

EXAMPLE XI

A lymphogram of a dog was made after injecting 5 milliliters of ExampleII subcutaneously. Poor to moderate visualization resulted. In anotherlymphogram 2 milliliters of Example II was injected intralymphaticallyinto the right side and 1 ml. into the left side of a dog. The contrastmedium did not pass the popliteal lymph node.

EXAMPLE XII

A bronchogram of a dog was made after administering Example III inpowder form via a Murphy endotracheal tube using a DeVilbiss powderblower, oxygen tank and polyethylene tube. The opacity and homogenitywas poor and the coating was fair. In another study 3 gms of powder gavepoor to fair opacity lasting at least 2 hours. Less than one gram wasretained in the lungs.

As various changes could be made in the above invention withoutdeparting from its scope it is to be understood therefore that theinvention is not limited except as defined by the appended claims.

What is claimed is:
 1. A compound represented by the following formula:##STR8## wherein a is an integer from 1 to 3, b is 0 or 1, R is phenyl,R₁ is ##STR9## wherein R₂ is hydrogen and R₃ is lower alkyl and X and Yare individually nonionizing functions compatible with low toxicityand/or water solubility in the 2,4,6-triiodophenyl configurationselected from the group consisting of hydrogen, lower acylamino,carbamyl, N-(lower alkyl)carbamyl and amino at least one of X and Ybeing other than hydrogen.
 2. Ethoxymethyl3-Acetamido-2,4,6-triiodobenzoate.
 3. Ethoxymethyl3-Acetamido-N-methyl-2,4,6-triiodoisophthalamate.
 4. Ethoxymethyl3-(3-Amino-2,4,6-triiodo-N-phenyl-benzamido)-propionate.